Collagens are a class of extracellular matrix proteins that represent 30% of total body protein and shape the structure of tendons, bones, and connective tissues. Abnormal or excessive accumulation of collagen in organs such as the liver, lungs, kidneys, or breasts, and vasculature can lead to fibrosis of such organs (e.g., cirrhosis of the liver), lesions in the vasculature or breasts, collagen-induced arthritis, Dupuytren's disease, rheumatoid arthritis, and other collagen vascular diseases. It would be useful to have both therapeutic and diagnostic agents that could assist in the treatment or diagnosis of such disorders.
Diagnostic imaging techniques, such as magnetic resonance imaging (MRI), X-ray, nuclear radiopharmaceutical imaging, ultraviolet-visible-infrared light imaging, and ultrasound, have been used in medical diagnosis for a number of years. Contrast media additionally have been used to improve or increase the resolution of the image or to provide specific diagnostic information.
Complexes between gadolinium or other paramagnetic ions and organic ligands are widely used to enhance and improve MRI contrast. Gadolinium complexes increase contrast by increasing the nuclear magnetic relaxation rates of protons found in the water molecules that are accessible to the diagnostic compositions during MRI (Caravan, P., et al., Chem. Rev. 99, 2293 (1999)). The relaxation rate of the protons in these water molecules increases relative to protons in other water molecules that are not accessible to the diagnostic composition. This change in relaxation rate leads to improved contrast of the images. In addition, this increase in relaxation rate within a specific population of water molecule protons can result in an ability to collect more image data in a given amount of time. This in turn results in an improved signal to noise ratio.
Imaging may also be performed using light, in which case an optical dye is chosen to provide signal. In particular, light in the 600-1300 nm (visible to near-infrared) range passes relatively easily through biological tissues and can be used for imaging purposes. The light that is transmitted through, or scattered by, reflected, or re-emitted (fluorescence), is detected and an image generated. Changes in the absorbance, reflectance, or fluorescence characteristics of a dye, including an increase or decrease in the number of absorbance peaks or a change in their wavelength maxima, may occur upon binding to a biological target, thus providing additional tissue contrast. In some situations, for example the diagnosis of disease close to the body surface, UV or visible light may also be used.
Ischemic heart disease is a leading cause of death in the developed world. Efforts in the detection of the disease often focus on the patency of major blood vessels such as the coronary arteries, and recent paradigms have emphasized the importance of the coronary microvasculature in providing blood flow, including collateral blood flow, to injured myocardial tissue. Since cardiac catheterization assessing the patency of coronary arteries is an expensive and risky procedure, noninvasive techniques that assess the likelihood of coronary artery disease have flourished, especially nuclear medicine based myocardial perfusion studies.
The most widely used techniques for measuring myocardial perfusion are SPECT (single photon computed tomography) imaging protocols using injectable nuclear agents (e.g., “hot” radiotracers), such as thallium isotope or technetium Sestamibi (MIBI). Frequently the patient is required to undergo a stress test (e.g., a treadmill exercise stress test) to aid in the SPECT evaluation of myocardial perfusion. The cardiac effect of exercise stress can also be simulated pharmacologically by the intravenous administration of a coronary vasodilator. Typically, after injection of the nuclear agent during stress, the myocardium is imaged. A second redistribution rest image is then obtained after an appropriate rest period (approximately 3-4 hours). Alternatively, the patient may be given a second, 2× concentrated dose of the nuclear agent during the rest phase and a second rest image is then acquired. The clinician compares the two image sets to diagnose ischemic areas as “cold” spots on the stress image. SPECT imaging, however, may result in inconclusive perfusion data due to attenuation artifacts and/or from the relatively low spatial resolution compared to other modalities. For instance, subendocardial defects may not be adequately visualized. Moreover, SPECT imaging exposes the patient to ionizing radiation.
Recently, magnetic resonance imaging (MRI) techniques have also been proposed to assess myocardial perfusion. In general, MRI is appealing because of its noninvasive character, ability to provide improved spatial resolution, and ability to derive other important measures of cardiac performance, including cardiac morphology, wall motion and ejection fraction in a single sitting. Current MRI perfusion imaging techniques require rapid imaging of the myocardium during the first pass (after bolus injection) of an extracellular fluid (ECF) or intravascular MR diagnostic composition; this technique is referred to as MRFP (magnetic resonance first pass) perfusion imaging. On T1-weighted images, the ischemic zones appear with a delayed and lower signal enhancement (e.g., hypointensity) as compared with normally perfused myocardium. Myocardial signal intensity versus time curves can then be analyzed to extract perfusion parameters. Intensity differences, however, rapidly decrease as the MR diagnostic composition is diluted in the systemic circulation after the first pass. Furthermore, because of the rapid timing requirement of MRFP perfusion imaging, the patient must undergo pharmacologically-induced stress while positioned inside the MRI apparatus. Rapid imaging may also limit the resolution of the perfusion maps obtained and may result in poor quantification of perfusion.
Because ischemically-injured myocardium contains both reversibly and irreversibly injured regions, accurate characterization of myocardial injury, in particular the differentiation between non-viable, necrotic (necrotic, acutely infarcted myocardium or chronically infarcted myocardium), ischemic, and viable myocardial tissue, is an important factor in proper patient management. This characterization can be aided by an analysis of the perfusion and/or reperfusion state of myocardial tissue adjacent to coronary microvessels either before or after an ischemic event (e.g., an acute myocardial infarction).